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2025-12-01

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cc-by (c) Kotmayer, L. et al., 2025
Please use this identifier to cite or link to this item: https://hdl.handle.net/2445/222921

Age-dependent phenotypic and molecular evolution of pediatric MDS arising from GATA2 deficiency

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https://doi.org/10.1038/s41408-025-01309-6

Abstract

GATA2 deficiency is an autosomal dominant transcriptopathy disorder with high risk for myelodysplastic syndrome (MDS). To elucidate genotype-phenotype associations and identify new genetic risk factors for MDS, we analyzed 218 individuals with germline heterozygous GATA2 variants. We observed striking age-dependent incidence patterns in GATA2-related MDS (GATA2-MDS), with MDS being absent in infants, rare before age 6 years, and steeply increasing in older children. Among 108 distinct GATA2 variants (67 novel), null mutations conferred a 1.7-fold increased risk for MDS, had earlier MDS onset compared to other variants (12.2 vs. 14.6 years, p = 0.009) and were associated with lymphedema and deafness. In contrast, intron 4 variants exhibited reduced penetrance and lower risk for MDS development. Analysis of the somatic landscape revealed unique patterns of clonal hematopoiesis. SETBP1 mutations occurred exclusively in patients with monosomy 7 and their frequency decreased with age. Conversely, the frequency of STAG2 mutations and trisomy 8 increased with age and appeared protective against early development of advanced MDS. Overall, the majority (73.9%) of mutation-positive cases harbored monosomy 7, suggesting it serves as a major driver in malignant progression. Our findings provide evidence for age-appropriate surveillance, and a foundation for genotype-driven risk stratification in GATA2 deficiency.

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Proteïnes, Hematologia pediàtrica, Malalties hematològiques, Mutació (Biologia)

Subject (English)

Proteins, Pediatric hematology, Hematologic diseases, Mutation (Biology)

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Articles publicats en revistes (Patologia i Terapèutica Experimental)
Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

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KOTMAYER, Lili, et al. Age-dependent phenotypic and molecular evolution of pediatric MDS arising from GATA2 deficiency. Blood Cancer Journal. 2025. Vol. 15, num. 1. ISSN 2044-5385. [consulted: 9 of June of 2026]. Available at: https://hdl.handle.net/2445/222921

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